The present invention relates to the reduction of breast cancer risk, and, in particular, to methods and devices for influencing the transport of carotenoids and possibly other substances from the blood into the breast microenvironment.
Breast cancer is one of the leading causes of disease and death in women, with greater than 90% of breast cancer originating in the epithelial cells of ducts (American Cancer Society, 1996a). Early detection and treatment of breast cancer has focused on improving prognosis and increasing the survival rates, still such rates have only plateaued (American Cancer Society, 1996d). As a result, women""s health experts have instigated a renewed focus and call for innovation in breast cancer prevention efforts (Love, 1995).
The protective effect of lactation and dietary carotenoids in breast cancer development has been supported (American Cancer Society, 1996a; Holmes, Hunter, and Willett, 1995; Stoll, 996; Weisburger, 1991). Little is known, however, about the influence the naturally-occurring physiologic process of lactation has on the microenvironment of the breast in relation to breast cancer prevention. Less is known about the presence of carotenoids in the microenvironment of the breast. No information is available on how lactation might influence transport of carotenoids into the microenvironment of the breast. Yet, lactation and diet as protective or chemopreventive processes represent health choices for women to prevent breast cancer.
The presence of fluid in the breast has been confirmed by history in the breast has been confirmed by histological study of the breast ductal system (Petrakis et al., 1975), and breast fluid has been obtained through manual aspiration from parous and nulliparous women (Petrakis et al., 1975; Sartorius, 1973, Sartorius, Smith, Morris, Benedict, and Friesen, 1977). Sartorious (1973) first reported the use of a suction device to aspirate breast fluid in a report on devising methods to detect breast cancer by studying cells from the breast fluid.
Petrakis et al. (1975, 1986, 1988a, 1988b, 1989, 1990), Sartorius et al. (1977), Visozo et al. (1992), and Wrensch et al. (1990) have conducted several studies ranging from clinical availability of breast secretions, descriptions of breast fluid regarding content, to epidemiologic investigations into cytologic changes and breast disease. These studies have supported that the epithelial lining of the breast ducts exist in a fluid environment that reflects the internal and external environment of the human. Murrell (1991) has hypothesized that under normal physiologic conditions, damage to breast epithelium by carcinogens as products of oxygen free radicals, in the absence of stimulus to clear fluid containing carcinogens, may expose the breast to increased risk of cancer development.
During the physiologic process of lactation, the fluid microenvironment of the breast is in a repetitious process of fluid synthesis and drainage. Changes in the breast epithelium lining the ducts during differentiation and growth in preparation for milk production is thought to alter the susceptibility of the cell to neoplastic changes (McTiernan and Thomas, 1986; Taylor-Papadimitriou, Lane, and Change, 1983). Furthermore, lactation acting as a mechanical cleansing process, flushes potential carcinogens in the ducts, which may represent another way in which lactation decreases risk of breast cancer (McTiernan and Thomas, 1986; Murrell, 1991; Yoo, et al., 1992). Malhotra (1977) points out that an alkaline milieu at the breast epithelial cell level results in increased mitotic activity and cell proliferation, which is carcinogenic. Stasis in the fluid environment of the breast, which can specifically occur during lactation failure, maintains the alkalinity of the cell environment. Nipple stimulation, which would likely increase oxytocin levels and lead to drainage of the breast, may be instrumental in preventing breast disease (Murrell, 1991).
While past studies on the protective effect of lactation on breast cancer risk report mixed results from nonconsequential (Haagensen et al., 1981; Kvale and Heuch, 1987; MacMahon et al., 1970) to moderate (Adami et al., 1990; Ing, Ho, and Petrakis, 1977; Levin, Sheehe, Graham, and Glidwell, 1964; Malhotra, 1977; McTierman and Thomas, 1986; Siskind et al., 1988), results from several contemporary studies support an association between lactation and decreased breast cancer risk, suggesting an independent, protective effect (Byers et al., 1985; Layde et al., 1988; Lubin et al., 1992; Newcomb et al., 1994; Yoo et al., 1992; Yuan et al., 1988). Most studies did not operationalize lactation other than in a dichotomous fashion (yes/no). Cumulative length of lactation can vary greatly among women.
Carotenoids are a group of related chemicals and natural lipid-soluble pigments found mainly in plants, certain vegetables, and in animal tissue (Britton, Liaaen-Jansen, and Pfander, 1995; DeLuca, 1978; Michnovicz and Klein, 1994) and serve as precursors of vitamin A. Of the carotenoids with provitamin A activity, beta-carotene xe2x80x9cis the most common and most effectivexe2x80x9d (Pitt, 1985, p. 8), thus beta-carotene has become the focus of interest as a significant biologically-active nutritional and anticarcinogenic substances (Burton, 1989; Byers and Perry, 1992; Dimascio, Murphy, and Sies, 1991). The main function of antioxidant nutrition, which includes lipid-soluble molecules such as carotenoids and enzymes derived from minerals, is to prevent oxidative damage to cells and their physiological function. Beta-carotene is the major carotenoid precursor of vitamin A and is the most effective, naturally occurring single oxygen quencher (Bendich, Phillips, and Tengerdy, 1990; Burton, 1989; Burton and Ingold, 1984; Krinsky and Deneke, 1982).
Of 15 studies investigating the relationship between nutrient intake and risk of cancer, including breast cancer, six studies (Brisson et al. 1989; Katsouyanni et al. 1988; Knecht et al., 1990; Negri et al., 1995; Rohan, McMichael, and Bahurste, 1988; and Wald et al, 1984), reported a decreased risk of breast cancer with dietary intake of beta-carotene. In seven studies, (Basu et al., 1989; Ewertz and Gill, 1990; Hislop, 1990; Marubini et al., 1988; Paganini-Hill et al., 1978; Potishman et al., 1990; Van""tNeer et al., 1990), results did not support the protective effect of beta-carotene. However, methods used to index or provide beta carotene intake are fraught with error, such as controlling for cooking methods or lipid intake, which is necessary for utilization of beta carotene.
Patton, et al. (1990) identified and measured concentrations of carotenoids in human colostrum in women immediately postpartum, specifically alpha- and beta-carotene, lycopene, and beta-cryptoxanthin. The concentrations of these carotenoids were widely varied and decreased over the first week postpartum, suggesting a flushing and diluting effect of progressive lactation on substances that are normally stored in the resting breast. Covington, et al. (1998) reported the presence of carotenoids in post-weaned breast fluids. Additionally, length of time post-wean negatively influenced the carotenoid level in nipple aspirates, while cumulative duration of lactation was not significantly related to carotenoid levels.
Notwithstanding the extensive research which has been conducted in this field, there remains a need for an understanding of the role of intraductal fluid and in connection with the risk of breast cancer, as well as methods and devices for using that understanding to create an efficacious risk reduction regimen.
There is provided in accordance with one aspect of the present invention, a method of elevating intraductal carotenoid levels in a non-lactating breast in a patient. The method comprises the steps of removing intraductal breast fluid from the non-lactating breast over a predetermined regimen. Although any removal of intraductal breast fluid in accordance with the present invention may have some preventative effects, removal is preferably accomplished in a series such as at least once per month, preferably twice per month or once per week over a period of at least two to six months.
In one embodiment of the invention, the removing intraductal breast fluid comprises manual aspiration. Preferably, the removing step comprises the steps of applying suction and compression. In one embodiment, the method further comprises the step of applying heat. Preferably, the compression comprises peristaltic compression.
The method may additionally comprise the step of increasing the oxytocin level in the breast prior to the removing step. The oxytocin level may be increased by direct administration of oxytocin to the patient, and/or by nipple stimulation.
In accordance with a further aspect of the present invention, there is provided a method of removing intraductal breast fluid from a patient. The method comprises the steps of contacting the breast with a mechanical intraductal fluid aspiration device, and activating the device to apply peristaltic compression and suction to the breast during a period of non-lactation to removal intraductal breast fluid. Preferably, the method additionally comprises the step of applying heat from the device to the breast.
In accordance with another aspect of the present invention, there is provided a method of reducing the risk of cancer formation in the breast duct. The method comprises the steps of periodically removing intraductal breast fluid from the breast using a mechanical intraductal breast fluid removal device. This may maintain an elevated average carotenoid level in the breast fluid compared to the carotenoid level in the absence of intraductal breast fluid removal. Preferably, the elevated average carotenoid level is maintained for a period of at least about 30 and preferably at least about 90 days.
In accordance with a further aspect of the present invention, there is provided an intraductal breast fluid aspiration device. The device comprises a tissue contacting surface, defining a first concavity for receiving a breast and a second concavity for receiving a nipple. A driver is provided, for imparting compressive force on at least the portion of the tissue contacting surface defining the first concavity. A vacuum conduit is placed in communication with the second concavity, and a sample collector is in communication with the second concavity.
Preferably, the driver imparts peristaltic compressive force on the tissue contacting surface. In one embodiment, the driver comprises a motor. In another embodiment, the driver comprises at least one expandable chamber such as the area inside an inflatable and collapsible flexible bladder or tube. Preferably, a plurality of inflatable tubes are aligned such that sequential filling and emptying of the tubes provides a peristaltic compressive force on the tissue contacting surface. The intraductal breast fluid aspiration device may additionally be provided with a heat source, such as an ultrasonic transducer.
The sample collector in one embodiment comprises a hollow container, which may be removably attached to the aspiration device. Alternatively, the sample collector comprises an absorbent media or membrane. In one embodiment, the sample collector additionally comprises a binding system for binding at least one analyte of interest in the breast fluid. The binding system may be chemical or biochemical, such as a monoclonal or polyclonal antibody.
In accordance with a further aspect of the present invention, there is provided a portable, self-contained, intraductal fluid aspiration device. The device comprises a housing, and a breast interface carried by the housing. A vacuum source is provided in communication with the interface, and a compression driver is coupled to the interface. At least one control is provided, for controlling operation of the aspiration device. Preferably, the interface is removably connected to the housing. A fluid reservoir is preferably provided in communication with the interface, and the fluid reservoir may be permanent or removably attached to the housing.
In accordance with a further aspect of the present invention, there is provided an intraductal fluid aspiration device which is adapted for use in the physician office or other clinical setting. The device comprises a control unit, and a power head. A flexible control line connects the power head to the control unit. A disposable user interface is removably attached to the power head, and a vacuum source in the control unit is in communication with the user interface through the control line. A compression cycle generator is provided in force transmitting contact with the user interface. Preferably, the device further comprises an ultrasound transducer in the power head. A central processing unit is preferably provided in the control unit for controlling the delivery of heat, compression and suction through the user interface.
Further features and advantages of the present invention will become apparent from the detailed description of preferred embodiments which follows, when considered together with the attached drawings and claims.